Tetracyclines are an important class of antibiotics in agriculture and the clinic; however, their efficacy is threatened by increasing resistance. Resistance to tetracyclines can occur through efflux, ribosomal protection, or enzymatic inactivation.
The tetracycline destructases are a recently-discovered family of tetracycline-inactivating flavoenzymes from pathogens and soil metagenomes with a high potential for broad dissemination. Tetracycline-inactivating enzymes represent an alarming emerging mechanism of antibiotic resistance to a crucial class of antibiotics (i.e., tetracyclines) that have been used for decades in the clinic, agriculture, and aquaculture. While tetracycline-resistant pathogens have canonically employed the mechanisms of drug efflux and target modification, enzymatic inactivation of tetracyclines appears to be on the rise in ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).
What is needed, therefore, is tetracycline/tetracycline destructase inhibitor combination therapy to overcome resistance by enzyme inactivation.